Functional Disruption of Gli1-DNA Recognition via a Cobalt(III) Complex

Christopher R. Brue, Meghan W. Dukes, Meghan Masotti, Robert Holmgren*, Thomas J. Meade

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The aberrant activation of the Gli family of zinc finger transcription factors (ZFTFs) is associated with several types of human cancer, including medulloblastoma and basal cell carcinoma. We have reported the use of cobalt(III) Schiff-base complexes (Co(III)-sb) as potent inhibitors of ZFTFs in vivo. These complexes inhibit transcription by displacing the zinc finger domain‘s structural Zn(II) ion, destabilizing the alpha helix necessary for DNA recognition. Here, we describe the use of Co(III)-sb complexes for the selective inhibition of Gli1. Spectroscopic and computational studies of the Gli1 DNA binding domain found that Co(III)-sb displaced Zn(II) through direct coordination with the His residues of the Cys2His2 Zn(II) binding site. As a result, there is a dose-dependent degradation of the alpha-helix content in the DNA binding domain of Gli1 and corresponding inhibition of consensus sequence recognition. We conclude that this strategy is well suited for the development of new and potent inhibitors of Gli1.

Original languageEnglish (US)
Article numbere202200025
JournalChemMedChem
Volume17
Issue number8
DOIs
StatePublished - Apr 20 2022

Keywords

  • DNA recognition
  • cancer
  • cobalt
  • inhibitors
  • molecular dynamics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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